August 2017

COVER FEATURE

Steroids roundup
Off-label but not off-limits


by Stefanie Petrou Binder, MD, EyeWorld Contributing Writer


Dry eye disease
Source: Edward Holland, MD


Physicians say off-label drug use is a matter of good clinical practice in patients requiring long-term steroid therapy

Off-label drug use, i.e., used for indications other than those approved by the FDA, is often a necessary standard of care. The physician’s code of ethics is guided by patients’ best interests, with off-label options often representing the best feasible treatment alternative. EyeWorld spoke with three specialists about off-label drug use and the best available choices and delivery methods in their patients undergoing long-term steroid therapy.

Drug choice based on side effects

Roughly 50% of medications used routinely in ophthalmic practice are off-label.1 Edward Holland, MD, Cincinnati Eye Institute, Cincinnati, thinks that when using the drugs at their disposal, ophthalmologists need to make discerning treatment decisions based on the condition of the individual patient. “We have a variety of steroid options, and we make the decision of which one to use based on the potency of the side effects. For instance, if you’re most interested in managing severe inflammation, difluprednate is the most effective and potent topical steroid for severe inflammation like uveitis or corneal transplant rejection. If, however, you are treating a milder condition and you need a good steroid effect, but you’re treating long term and worry about side effects, you would choose a different steroid, such as loteprednol,” Dr. Holland explained.
Loteprednol is an ester steroid that is approved for treating inflammation after surgery, allergic inflammation, uveitis, and some chronic forms of keratitis. It is the only approved ester steroid and is efficacious without the IOP-raising effects of ketone steroids. “The benefit of difluprednate is that it is the most effective steroid, but the disadvantage is that it will cause a rise in IOP in approximately 10% of patients as the other ketone steroids,” Dr. Holland said. “We tend to choose the safest steroid for chronic use, unless we really need to treat severe inflammation.”

Graft rejection

Difluprednate has drastically changed ophthalmologists’ ability to manage graft rejection. “In the past, the gold standard steroids were prednisolone or dexamethasone, the two most potent steroids,” Dr. Holland said. “But we still had a significant number of patients who would break through, and we would either use intracameral preservative-free dexamethasone in chronic rejection patients or use oral immunosuppressive agents. But difluprednate used aggressively, either as a prophylaxis or as a treatment in acute endothelial rejection, has reduced our need to go to oral systemic immunosuppression because it is such a potent corticosteroid. It has been a tremendous adjunct for the corneal surgeon in preventing or reducing inflammation in patients.”
According to Henry Perry, MD, Long Island Surgicenter, Long Island, New York, the best drugs for treating acute graft rejection are corticosteroids, specifically prednisolone acetate 1% solution. However, drug choices in graft patients need to take IOP-raising effects into account. “In the mid 1990s I had several patients who had graft rejections and developed steroid-induced ocular hypertension. I performed a corneal transplant on a patient for keratoconus, and in order to maintain his graft, I kept him on corticosteroids. Unfortunately, his IOP kept increasing, in spite of maximal medical therapy. This led us to choose topical cyclosporine as an alternative to corticosteroids, using a 0.5% solution diluted from the 5% IV solution. We used cyclosporine as a substitute for corticosteroids, and by eliminating the corticosteroids, the patient’s IOP became normal and the cyclosporine was effective enough in terms of its anti-inflammatory action to maintain the clarity of the graft and prevent precipitates from returning.”
The case Dr. Perry described was part of a study conducted in 25 patients with post-keratoplasty glaucoma. The study revealed that 84% of the patients (n=21) had a reduced IOP, and all maintained graft clarity in the follow-up period of 3 to 12 months. Following the trial period, three patients discontinued one or more glaucoma medications.2

Dry eye

Dr. Perry has successfully used cyclosporine for a number of different indications. In a retrospective case series that he conducted in eight patients with chronic dry eye, he and his colleagues reported on the resolution of the symptoms of chronic dry eye following a minimum 6- to 72-month b.i.d. course of topical 0.05% cyclosporine. All eight patients experienced a complete resolution of dry eye. The study concluded that topical cyclosporine was a cure for the signs and symptoms of chronic dry eye, presumably associated with the elimination of the underlying inflammatory process.3
Cyclosporine works locally in the eye as a partial immune system modulator, increasing the eye’s natural ability to produce tears. Tear production is thought to decrease when lymphocytes die and accumulate in the lacrimal glands. Restasis (cyclosporine 0.05% ophthalmic emulsion, Allergan, Dublin, Ireland) effectively stops this process. “We have been using mainly Restasis to treat dry eye disease with relatively good success in the range of 80%. More recently, lifitegrast solution has come on the market, which has also been shown to be efficacious,” Dr. Perry said.
The main difference between Restasis and lifitegrast is their onset of action. Lifitegrast is effective within 2 weeks versus Restasis, which is effective in 3 to 6 months. Lifitegrast penetrates more rapidly, as a solution, however, it can burn and leave patients with a metallic taste in their mouth. Restasis can also burn but does not have an after taste. It has a positive effect for meibomian gland disease due to the anti-inflammatory effect, but also has a direct physical effect, with the emulsion helping pull out secretions from the meibomian glands.
“Since both of these compounds can be irritating, in very symptomatic patients, it is better to use a mild steroid, such as loteprednol [Lotemax, Bausch + Lomb, Bridgewater, New Jersey], a synthetic steroid,” Dr. Perry said. “We use it anywhere from 2 to 4 weeks and then taper. This regimen will quiet the anterior segment in most dry eye patients and allow us to give the Restasis and/or lifitegrast more of a chance to work in a better situation. To use them concurrently would be the best method. The use of either alone would not work as well and not be as user friendly, meaning patients would discontinue the drugs more frequently, without the use of steroids beforehand. In this use, Lotemax is used off-label.”
According to Barry Lee, MD, Eye Consultants of Atlanta, combining agents for best efficacy is a huge advantage. “I will often use topical ester steroids in concert with topical cyclosporine for decreasing the inflammation associated with dry eyes or meibomian gland disease. This often helps patients feel better in terms of dry eye symptoms since it may take several months to see improvement with topical cyclosporine. I think that ester steroids have less risk of inducing complications of ketone steroids, such as cataract and increased intraocular pressure. I typically use the gel formulation of ester steroids b.i.d. for 4 to 6 weeks and decrease to once a day for 2 to 3 weeks, and then discontinue once the topical cyclosporine takes effect. Now that topical lifitegrast is on the market, I will likely not need the steroids as often, since it seems to work faster than topical cyclosporine in improving symptoms of dry eye disease,” Dr. Lee said.
Dr. Lee will often use cyclosporine and lifitegrast in off-label conditions that involve T-cell mediated inflammatory reactions on the ocular surface, which often also require concurrent topical corticosteroids, such as for Thygeson’s, allergic eye disease, atopic and vernal conjunctivitis, giant papillary conjunctivitis, Terrien’s degeneration, superior limbic keratoconjunctivitis, post-surgical in patients undergoing keratolimbal allografts, keratoplasty, or severe dry eyes after cataract or refractive procedures. He begins dosing b.i.d. and increases to q.i.d. if he cannot get the inflammation under control.

Neovascularization

“We have an increasing amount of experience with off-label use of bevacizumab for the treatment of corneal neovascularization in the last few years,” Dr. Lee said. “I have delivered the drug via topical application (1%) q.i.d. Compounding pharmacies that can make the topical solution have become harder to find with increasing government regulations so I have switched to either subconjunctival or intracameral injection. Bevacizumab use avoids the side effects of topical steroids, but as soon as treatment is discontinued, the corneal neovascularization recurs.”
The occurrence of ocular and systemic adverse events, particularly in the neovascular area and the area of the corneal vessels, vessel caliber and diameter, and the fraction of the total corneal area invaded by vessels were greatly reduced in a prospective open label study that gave 1.0% bevacizumab for 3 weeks in 10 eyes with stable corneal neovascularization. The patients were followed for 24 weeks, and the study concluded that short-term topical bevacizumab therapy reduced the severity of corneal neovascularization without local or systemic side effects.4
Approaches to the treatment of corneal neovascularization may differ among specialists. According to Dr. Holland, the current use of bevacizumab for corneal neovascularization is a trend, effective in resolving the signs of neovascularization, but not in addressing the underlying cause. “Corneal neovascularization is never the primary disease—it is secondary to something such as inflammation or chronic epithelial problems. I see many patients who have recurrent anti-VEGF injections, but anti-VEGF does nothing to deal with the etiology of neovascularization. Aggressive treatment with anti-inflammatories will get the neovascularization to regress, and in cases with epithelial problems, aggressive therapy for epithelial disease will get the neovascularization to regress. In a very rare case, we will have addressed the etiology and still have a persistent leaky vessel, and that is one indication for an anti-VEGF injection. But what I see is that patients get recurrent anti- VEGF therapy, but they don’t have the etiology addressed. I think it is a rare case where you can’t control the neovascularization by pinpointing your therapy to the etiology. The vessel will regress with anti-VEGF, but the inflammation is still there. Stopping the neovascularization is not going to stop the corneal scarring. I do think there is often a disconnect in the way that clinicians are approaching corneal neovascularization,” he said.

Delivery

Dr. Holland administers steroids topically and will occasionally
administer subconjunctival dexamethasone in patients who are high risk for inflammation, which tends to be very safe and effective. He injects preservative-free dexamethasone intracamerally, into the anterior chamber, for best effects. Dr. Lee prefers topical drops after cataract surgery, and if he is concerned about postoperative inflammation/uveitis, he will give sub-Tenon’s capsule steroid injections in addition to topical steroids, topical NSAIDs, and topical antibiotics. Dr. Perry thinks injected steroids introduce an additional intraoperative step, which can lead to complications and endophthalmitis. “There are many other mistakes than can occur, such as mistakes in concentrations, and I think that topical use is sufficient,” he said. Dr. Perry finds the subconjunctival delivery method safe and just as effective as intraocular.

References

1. Ask the Ethicist: Off-Label Medications. EyeNet. May 2011.
2. Perry HD, et al. Topical cyclosporin A in the management of postkeratoplasty glaucoma. Cornea. 1997;16:284–8.
3. Wilson SE, et al. Long-term resolution of chronic dry eye symptoms and signs after topical cyclosporine treatment. Ophthalmology. 2007;114:76–9.
4. Dastjerdi MH, et al. Topical bevacizumab in the treatment of corneal neovascularization: results of a prospective, open-label, noncomparative study. Arch Ophthalmol. 2009;127:381–9.

Editors’ note: Drs. Holland, Lee, and Perry have no financial interests related to their comments.

Contact information

Holland: mredmond@CincinnatiEye.com
Lee: lee0003@aol.com
Perry: hperry@ocli.net

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